Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on Dec. 16, 2024. Claims 1-19 are pending and currently examined.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 1-19 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Base claim 1 recites:
A substrate or plurality of substrates comprising at least one peptide selected from a plurality of peptides attached to said substrate or plurality of substrates, the plurality of peptides selected from the group consisting of: i) a betacoronavirus ("BC") spike protein receptor binding domain (RBD) sequence; ii) a first BC spike protein C-terminus domain (CTD1) sequence that is optionally pep4; iii) a second BC spike protein C-terminus domain (CTD2) sequence that is optionally pep 1; iv) a BC spike protein Furin cleavage site (S1/S2) sequence that is optionally pep2; v) a BC spike protein S2' Fusion protein (S2'FP) sequence that is optionally pep5; vi) a BC spike protein 5' flanking Heptad Repeat-2 (5'fHR2) that is optionally pep6; vii) a BC spike protein Heptad Repeat-2 (HR2) that is optionally pep3; and combinations thereof.
This claim has at least the following issues:
A. The phrase “a betacoronavirus ("BC") spike protein receptor binding domain (RBD) sequence” is not clear. Since any stretch of two consecutive amino acid residues can form a “sequence”, it is not clear if the above limitation requires a functional RBD domain or any “sequence” from the RBD domain may suffice. This issue also exists in items (ii)-(v) which recite “a……sequence”.
B. Claim 1 recites “a first BC spike protein C-terminus domain (CTD1) sequence that is optionally pep4” and “a second BC spike protein C-terminus domain (CTD2) sequence that is optionally pep 1”. Table A of the Specification shows peptide sequences labeled C-terminus domain (CTD1), peptide 4, C-terminus domain (CTD2), and peptide 1, as well as others which are also recited in claim 1. These sequences align with a sequence in the SARS-CoV-2. See alignment below for “C-terminus domain (CTD1)” with sequence GSGSNKKFLPFQQFGRDIADTTDA (SEQ ID NO: 29).
surface glycoprotein [Severe acute respiratory syndrome coronavirus 2]
Sequence ID: UIC00486.1Length: 1273Number of Matches: 1
Range 1: 554 to 575GenPeptGraphicsNext MatchPrevious Match
Alignment statistics for match #1
Score Expect Identities Positives Gaps
72.7 bits(164) 6e-13 22/22(100%) 22/22(100%) 0/22(0%)
Query 3 GSNKKFLPFQQFGRDIADTTDA 24
GSNKKFLPFQQFGRDIADTTDA
Sbjct 554 GSNKKFLPFQQFGRDIADTTDA 575
However, claim 1 is generic for all betacoronavirus (BC) and does specify amino acid sequences for the recited peptides, with only pep1 to pep6 recited which are optional. Therefore, it is not clear what the metes and bounds are for the peptides i) to vii) recited in claim 1. E.g., it is not clear if the peptides shown in Table A are the claimed peptides, or just examples of the claimed peptides.
To facilitate examination, the peptides of claim 1 are considered to read on peptides comprising or comprised by sequences of a betacoronavirus (BC) spike protein with sequence features of the peptides defined in Table A. E.g., the item i) is considered as reading on a BC spike protein peptide comprising or comprised by a sequence homologous to SEQ ID NO: 20 (SARS-CoV-2 RBD).
Claim 4 recites “wherein the plurality of peptides comprises at least two of the RBD, pep3, pep5, and pep6”. Here, it is not clear what the metes and bounds of the limitation “the RBD” are. It appears that “the RBD” refers to “a betacoronavirus ("BC") spike protein receptor binding domain (RBD) sequence” claim 1 which claim 4 depends via claim 2.
Claims 17-18 recite “further comprising antibodies produced by the individual”. It is not clear how to interpret this limitation because claims 2 and 3 from which claims 17 and 18 depend do not recite an individual.
Claim Rejections - 35 USC § 102/103
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-2, 4, 6, 11-16 and 19 are rejected under 35 U.S.C. 102/103 as being unpatentable over Zhang et al. (Cell Res 30, 702–704 (2020)).
The base claim 1 is described and interpreted in the 112(b) rejection above. Briefly, the peptides of claim 1 are considered to read on peptides comprising or comprised by sequences of a betacoronavirus (BC) spike protein with sequence features of the peptides defined in Table A.
Zhang teaches a study on mining of epitopes on spike protein of SARS-CoV-2 from COVID-19 patients. Zhang teaches that in the study, the authors analyzed the correlation between S- or Nucleocapsid (N) protein-specific antibody levels and neutralizing antibody tires. Furthermore, they aimed to identify linear B cell linear immunodominant (ID) sites on the S protein by Pepscan analysis with a series of overlapped peptides against the sera from COVID-19 patients. See page 702, left column, para 1.
Zhang teaches that the authors profiled IgG/IgM/IgA levels against the S and N proteins in the sera of COVID-19 patients (Supplementary information, Fig. S1a–f). All serum samples from COVID-19 patients tested positive for SARS-CoV-2 were assayed by ELISA using plates coated with SARS-CoV-2 lysates (Fig. 1a). All convalescent sera from the COVID-19 patients contained specific IgG antibodies against recombinant SARS-CoV-2 N protein, but not all hospitalized patient sera had specific IgG antibodies for the RBD fragment of the S protein due to their early infection stage. The relatively high immunogenicity of SARS-CoV-2 N protein during infection showed it has potential as an antigen for developing COVID-19 diagnostics (Supplementary information, Fig. S1d–f). However, the amounts of the different antibodies varied across patients. The authors found that IgM contributed 5%–34% of N protein-specific antibodies, whereas anti-RBD IgM contributed 10%–49% of RBD-specific antibodies (Supplementary information, Fig. S1g, h). See page 702, left column, para 2.
Zhang teaches that all peptides were manufactured by GL Biochem (Shanghai) Ltd in the form of a dry powder. The peptides were generated using solid phase synthesis methods and the quality of the products was monitored by mass spectrometry. Three groups of peptides (106-160, 365-374, and 687-741) of the S protein could not be synthesized by this current method. All peptides were dissolved in pH 7.4 PBS buffer or 8 M pH 7.0 urea Na2HPO4/NaH2PO4 buffer. See supplemental information, page 2, “Synthesis of peptides”.
Zhang teaches that epitope-specific antibodies were detected by enzyme-linked immunosorbent assay (ELISA). Briefly, all peptides or recombinant proteins at a final concentration of 0.5 μg/mL in 50 mM coating buffer (pH 9.6 Na2CO3/NaHCO3) were coated on ELISA plates (Nunc, Roskilde, Denmark) and incubated overnight at 4°C. Plates were blocked with TBS-5% (w/v) non-fat milk for 3 h at 37°C and washed four times in 0.05% Tween-20 (Sigma) in TBST. Diluted patient or mice sera were added into the wells and incubated for 1 h at 37°C. Plates were washed six times in TBS-0.05% Tween and incubated with horseradish peroxidase (HRP)-conjugated goat anti-mouse IgG (ThermoFisher, Catalog # 31410), goat anti-human IgM (ThermoFisher, Catalog # A18841), or goat anti-human IgA (ThermoFisher, Catalog # A18781) for 1 h at 37°C. The colour was developed using trimethyl borane (TMB) solution (Sigma) and absorbance was measured at 450 nm using an ELISA reader. See supplemental information, page 3, “Antibody detection using ELISA”.
Table S1 shows a list of synthesized spike protein peptides used in the study. See below:
PNG
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1060
582
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Greyscale
The peptides above include ones that comprise or are comprised in the peptides shown in Table A of the current application. E.g., peptides spanning positions 330-521 are comprised in the receptor binding domain (RBD) in Table A; peptide 662-686 (CDIPIGAGICASYQTQTNSPRRARS) comprises the majority of Peptide 2 (ASYQTQTNSPRRARSV (SEQ ID NO, 24) and furin cleavage site (S1/S2) (GSGSASYQTQTNSPRRARSV (SEQ ID NO, 25)) shown in Table A, etc.
Accordingly, Zhang teaches an ELISA assay for detection of serum antibodies using SARS-CoV-2 antigens coated on ELISA plates, such antigens including whole virus lysate, recombinantly expressed RBD peptide, and synthesized overlapping peptides covering the majority of the spike protein. Here, each well of the ELISA plate can be considered as a substrate to which an antigen is coated. Indeed, the specification teaches “[T]he substrate can be any suitable substrate onto which one or more described peptides can be attached. Examples include substrates typically used in immunodetection assays, lateral flow devices, bead-based assays, microfluidic devices, etc.” See [0045].
Zhang is silent on how many different peptides are coated on the ELISA plate except that at least one antigen is used. However, based on the teachings of Zhang that multiple different SARS-CoV-2 antigens are used in the study, one of skill in the art would have found it obvious to coat an ELISA plate (which may contain 96 or more wells) with multiple different antigen peptides, one antigen peptide per well, so that antibody reactions to different epitopes could be differentiated.
Regarding claims 4 and 6, the peptide 802-826 (FSQILPDPSKPSKRSFIEDLLFNKV) in Table S1 of Zhang comprise the Peptide 5 (ILPDPSKPSKRSFIEDLLF (SEQ ID NO: 30)) shown in Table A.
Regarding Claims 11-16 which further specify that substrate of claim 2 is in contact with a sample obtained from an individual, Zhang teaches that serum samples from SARS-CoV-2 patients (hospitalized and discharged) and healthy donors were tested in the study by ELISA. See Fig. 1 legend. As to the limitations on when or at what stage of infection the sample was obtained, one of skill in the art would have found it obvious to test samples of patients at any stage of infection or vaccination (before or after) based on study needs for assessment of antibody response.
Accordingly, Zhang anticipates or makes obvious claims 1-2, 4, 6, 11-16 and 19.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-19 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (Cell Res 30, 702–704 (2020)), as applied above, Xu et al. (US 2024/0207401 A1, published on Jun. 27, 2024; PCT filed on Mar. 19, 2021), He et al. (J Med Virol. 2021; 93:2115–2131; published online February 17, 2021), and GenBank: MN908947.3. (Severe acute respiratory syndrome coronavirus 2 isolate Wuhan-Hu-1, complete genome. Dated Mar. 18, 2020).
Claims 1-2, 4, 6, 11-16 and 19 are described above. Claims 3 and 17-18 further specify that the at least one of the peptides is modified to include at least one linker amino acid sequence. Claims 5 and 7-10 specify pep3 and/or pep6.
Relevance of Zhang is set forth above.
Xu teaches an invention above antibodies specific to the spike proteins of coronaviruses, such as SARS-CoV, MERS-CoV and SARS-CoV-2 and methods of making and using the antibodies. See Abstract.
Fig. 14 of Xu shows the binding affinity of the antibodies and epitope mapping of the mAbs. A). Microscale thermophoresis (MST)-binding curves using purified mAbs versus fluorescently labeled SARS-CoV, MERS-CoV and SARS-CoV spike trimer. Normalized fluorescence was calculated using NanoTemper Analysis 1.2.101 and is plotted as function of mAb concentration. The effective half maximal binding (EC50) was calculated by non-linear regression of the hill equation in Prism 8.4.3. N=3 B). Antibody epitopes were defined by cross-inhibition for binding. The CR3022 was used as a guide mAb to distinguish anti-RBD antibodies. The influenza and ebola antibodies were used as noninhibiting controls. The mAbs cloned from the patients were used to test the inhibition effect of each other by ELISA as described in methods below. Red designates inhibition of the biotinylated antibody to the competing antibody while green designates the absence of inhibition. N=3 C). The selected mAbs were screened against a library of overlapping peptides that covers the SARS-CoV-2 spike. D). The peptides that were recognized are represented on the structure of SARS-CoV spike monomer. PDB: 6VXX, E). Shows embodiments of Pl and P2 epitopes in the spike protein S2 domain in each of SARS-CoV, MERS-CoV and SARS-CoV. See [0428].
Accordingly, Xu teaches a method of screening antibodies against SARS-CoV-2 using a panel of overlapping peptides that cover the Spike protein.
He teaches a study for vaccine design based on 16 epitopes of SARS-CoV-2 spike protein. In this study, 66 epitopes containing pentapeptides of SARS‐CoV‐2 spike protein in the IEDB database were compared with the amino acid sequence of SARS‐CoV‐2 spike protein, and 66 potentially immune‐related peptides of SARS‐CoV‐2 spike protein were obtained. Based on the single‐nucleotide polymorphisms analysis of spike protein of 1218 SARS‐CoV‐2 isolates, 52 easily mutated sites were identified and used for vaccine epitope screening. The best vaccine candidate epitopes in the 66 peptides of SARS‐CoV‐2 spike protein were screened out through mutation and immunoinformatics analysis. The best candidate epitopes were connected by different linkers in silico to obtain vaccine candidate sequences. The results showed that 16 epitopes were relatively conservative, immunological, nontoxic, and nonallergenic, could induce the secretion of cytokines, and were more likely to be exposed on the surface of the spike protein. They were both B‐ and T‐cell epitopes, and could recognize a certain number of HLA molecules and had high coverage rates in different populations. Moreover, epitopes 897‐913 were predicted to have possible cross-immunoprotection for SARS‐CoV and SARS‐CoV‐2. The results of vaccine candidate sequences screening suggested that sequences (without linker, with linker GGGSGGG, EAAAK, GPGPG, and KK, respectively) were the best. The proteins translated by these sequences were relatively stable, with a high antigenic index and good biological activity. The study provided vaccine candidate epitopes and sequences for the research of the SARS‐CoV‐2 vaccine. See Abstract.
He teaches that after comparing the amino acid sequences of 66 epitopes in the IEDB database with those of corresponding positions of SARS‐CoV‐2 spike protein, 66 peptides belonging to SARS‐CoV‐2 spike protein were obtained and shown in Table 1. Among the obtained 66 peptides of SARS‐CoV‐2 spike protein, six peptides (310‐317, 757‐764, 891‐907, 897‐913, 899‐906, and 1025‐1041) were completely consistent with the sequences of epitopes in the IEDB database, which are bolded in Table 1. Moreover, there were seven peptides (356‐372, 356‐373, 365‐381, 371‐387, 373‐389, 379‐395, and 418‐434) partially overlapped with CR3022 epitope of SARS‐CoV‐2 published in Science by Yuan et al., which are underlined in Table 1. CR3022 is a neutralizing antibody previously isolated from a convalescent SARS patient and targets a highly conserved epitope that enables cross‐reactive binding between SARS‐CoV and SARS‐CoV‐2. CR3022 related epitopes may produce cross‐protective antibody responses against SARS‐CoV and SARS‐CoV‐2. Therefore, these peptides need to be focused on in subsequent experiments. See page 2117, left column, para 2.
Accordingly, He teaches a study that identifies peptides in SARS-CoV-2 S protein that contain immune epitopes that have the potential to be used as vaccine antigens.
GenBank: MN908947.3 discloses the complete genome of Severe acute respiratory syndrome coronavirus 2 isolate Wuhan-Hu-1, including the amino acid sequence of the S protein, indicating that the S protein of SARS-CoV-2 in publicly available at the time of invention.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the current invention to combine the teachings of Zhang, Xu, He, and GenBank: MN908947.3 to arrive at the invention as claimed. One would have been motivated to do so to establish a more complete antibody detection/screening assay, than those taught in Zhang and Xu, by including additional peptide antigens derived from SARS-CoV-2 S protein.
Regarding claims 3 and 17-18, He teaches antigen peptides may be with linkers. See Abstract. Further regarding claim 18, Zhang teaches that horseradish peroxidase (HRP)-conjugated goat anti-mouse IgG, goat anti-human IgM, or goat anti-human IgA can be used in the ELISA assay, as the secondary antibody, for the detection of antibodies in test sample.
Regarding claims 5 and 7-10 which further specify pep3 and/or pep6, pep3 and pep6 correspond to sequences of the SARS-CoV-2 S protein of aa positions 1179-1213 (pep3) and 1143-1167 (pep6) respectively, as aligned with the S sequence disclosed in GenBank: MN908947.3. One of skill in the art would have found it obvious to include peptides derived from the S protein regions corresponding to the pep3 and pep6 sequences so that antibodies bind to these regions can also be detected/screened.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NIANXIANG (NICK) ZOU whose telephone number is (571)272-2850. The examiner can normally be reached on Monday - Friday, 8:30 am - 5:00 pm, EST. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MICHAEL ALLEN, on (571) 270-3497, can be reached. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/NIANXIANG ZOU/
Primary Examiner, Art Unit 1671
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